The E280A presenilin 1 Alzheimer mutation produces increased A42 deposition and severe cerebellar pathology

Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early−onset familial Alzheimer's disease (FAD)^1,2 and are associated with increased levels of amyloid −peptides (A) ending at residue 42 (A42) in plasma and skin fibroblast media of gene carriers³. A42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1−FAD patients from a large Colombian kindred⁵ bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation². Using antibodies specific to the alternative carboxy−termini of A, we detected massive deposition of A42, the earliest and predominant form of plaque A to occur in AD (ref. 6−8), in many brain regions. Computer−assisted quantification revealed a significant increase in A42, but not A40, burden in the brains from 4 PS1−FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous A42−reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased A42 levels in PS1−FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the −amyloid precursor protein at the C−terminus of A to favor deposition of A42

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